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Summary: Background: Filgotinib, an oral, once‐daily, Janus kinase 1 preferential inhibitor, is an approved treatment for moderately to severely active ulcerative colitis. Aims: The aim of this study is to assess the safety and efficacy of continued filgotinib therapy over ~4 years in the long‐term extension of the phase 2b/3 SELECTION trial (SELECTIONLTE; NCT02914535). Methods: In this interim analysis of SELECTIONLTE, SELECTION completers (week 10 responders to filgotinib who completed the maintenance study) continued their assigned treatment (double‐blind filgotinib 200 mg [FIL200] or filgotinib 100 mg) and SELECTION week 10 non‐responders received open‐label FIL200. We assessed safety by adverse events (AEs), and efficacy by partial Mayo Clinic Score (pMCS), inflammatory biomarkers and health‐related quality of life (HRQoL). We compared safety and efficacy between achievers and non‐achievers of a multi‐component endpoint, comprehensive disease control (CDC), comprising symptomatic, endoscopic, inflammatory biomarker and HRQoL improvements. Results: Data for completers (n = 250) and non‐responders (n = 372) were reported for ≤202 weeks. AE occurrences were low and consistent with previous analyses. The as‐observed proportion of FIL200‐treated patients in pMCS, biomarker and HRQoL remission during SELECTIONLTE remained high among completers (week 144: 80.0%, 86.4% and 86.0%, respectively) and increased among non‐responders (week 192: 62.1%, 76.7% and 59.3%, respectively). Significantly higher proportions of CDC achievers at SELECTION week 58 achieved pMCS, IBDQ and corticosteroid‐free pMCS remission than non‐achievers, up to LTE week 96. Conclusions: Filgotinib induced and maintained symptomatic remission and improved HRQoL over 4 years. Safety results showed a proven long‐term benefit–risk profile. FIL200‐treated CDC achievers had better long‐term outcomes than non‐achievers. [ABSTRACT FROM AUTHOR]

Summary Background Aim Methods Results Conclusions Risankizumab is efficacious and well tolerated in adults with moderately to severely active Crohn's disease (CD).To evaluate the corticosteroid‐sparing effect of risankizumab in CD.During the 12‐week induction period, patients maintained stable baseline corticosteroid doses, up to 20 mg/day prednisone or equivalent. At week 0 of maintenance, a mandatory corticosteroid taper was started. This post hoc analysis evaluated corticosteroid‐free clinical and endoscopic outcomes at week 52 of maintenance; safety was also assessed.Of 889 patients randomised to induction with risankizumab 600 mg or placebo, 285 (32.1%) were taking baseline concomitant corticosteroids. Week 12 clinical remission and endoscopic response rates were greater for risankizumab 600 mg versus placebo, regardless of concomitant corticosteroid use. At week 52, 66.7%, 50.0% and 41.2% of patients taking risankizumab 180 mg, risankizumab 360 mg and (withdrawal) placebo, respectively, discontinued corticosteroids. Week 52 corticosteroid‐free clinical remission per stool frequency/abdominal pain score (risankizumab 180 mg [42.7%] or 360 mg [49.8%]; [withdrawal] placebo [39.0%]), corticosteroid‐free clinical remission per Crohn's Disease Activity Index (risankizumab 180 mg [51.0%] or 360 mg [49.5%]; [withdrawal] placebo [40.2%]), and corticosteroid‐free endoscopic response (risankizumab 180 mg [44.6%] or 360 mg [44.7%]; [withdrawal] placebo [20.7%]) rates were greater for risankizumab than placebo. Adverse event rates were generally similar, regardless of baseline corticosteroid use.Efficacy of risankizumab 600 mg induction therapy was independent of concomitant corticosteroid use. Risankizumab 180 and 360 mg maintenance therapy yielded high rates of corticosteroid‐free clinical and endoscopic outcomes at week 52. [ABSTRACT FROM AUTHOR]

Etrasimod is an investigational, once‐daily, oral, selective sphingosine 1‐phosphate receptor 1,4,5 modulator in development for immune‐mediated inflammatory diseases (IMIDs). Here, we report the human safety, pharmacokinetics, and pharmacodynamics of etrasimod obtained from both a single ascending dose (SAD; 0.1‐5 mg) study and a multiple ascending dose (MAD; 0.35‐3 mg once daily) study. Overall, 99 healthy volunteers (SAD n = 40, MAD n = 59) completed the 2 studies. Evaluated single and multiple doses were well tolerated up to 3 mg without severe adverse events (AEs). Gastrointestinal disorders were the most common etrasimod‐related AEs. Over the evaluated single‐ and multiple‐dose ranges, dose‐proportional and marginally greater‐than‐dose‐proportional etrasimod plasma exposure were observed, respectively. At steady state, etrasimod oral clearance and half‐life mean values ranged from 1.0 to 1.2 L/h and 29.7 to 36.4 hours, respectively. Dose‐dependent total peripheral lymphocyte reductions occurred following etrasimod single and multiple dosing. Etrasimod multiple dosing resulted in reductions from baseline in total lymphocyte counts ranging from 41.1% to 68.8% after 21 days. Lymphocyte counts returned to normal range within 7 days following treatment discontinuation. Heart rate lowering from pretreatment baseline on etrasimod dosing was typically mild, with mean reductions seen after the first dose of up to 19.5 bpm (5 mg dose). The favorable safety, pharmacokinetic, and pharmacodynamic properties of etrasimod in humans supported its further development and warranted its investigation for treatment of IMIDs. [ABSTRACT FROM AUTHOR]

Olamkicept selectively inhibits the cytokine interleukin‐6 (IL‐6) trans‐signaling pathway without blocking the classic pathway and is a promising immunoregulatory therapy for inflammatory bowel disease (IBD). These first‐in‐human, randomized, placebo‐controlled, single‐ (SAD) and multiple‐ascending dose (MAD) trials evaluated olamkicept safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics. Doses tested in the SAD trial included seven single intravenous doses (0.75, 7.5, 75, 150, 300, 600, and 750 mg) and one subcutaneous (SC) dose (60 mg) given to healthy subjects (N = 64), and three intravenous doses (75 mg, 300 mg, and 750 mg) given to patients with Crohn's disease (CD; N = 24). Doses tested in the MAD trial included multiple intravenous doses (75, 300, and 600 mg once weekly for 4 weeks) given to healthy subjects (N = 24). No severe or serious treatment‐emergent adverse events (TEAEs) were recorded. The most common TEAEs were headache, nasopharyngitis, and myalgia in the SAD trial, and diarrhea, headache, and cough in the MAD trial. Infusion‐related reactions occurred in one and two subjects in the SAD and MAD trial, respectively, leading to treatment discontinuation in the MAD trial. Olamkicept showed dose‐independent pharmacokinetics after single and multiple administrations, and there was no major difference in systemic exposure between healthy subjects and patients with CD. Complete target engagement (inhibition of phosphorylation of signal transducer and activator of transcription‐3) was achieved in blood around or above olamkicept serum concentrations of 1–5 μg/mL. Overall, these results suggest that olamkicept is safe and well‐tolerated in healthy subjects and patients with CD after single intravenous/SC and multiple intravenous administrations. [ABSTRACT FROM AUTHOR]

Summary: Background: IBDBIO‐ASSIST was a randomised controlled trial assessing the efficacy of care provided by IBD nurse specialists in Germany in improving health‐related quality of life (QoL) in IBD patients on biologic therapy. Aim: To evaluate patient‐related outcomes and economic consequences associated with integrating IBD nurses into usual care. Methods: We randomly assigned 1086 patients with IBD on biologic therapy to a control group (CG) receiving usual care or an intervention group (IG) receiving additional care from an IBD nurse specialist. The primary outcome was disease‐specific QoL (sIBDQ) assessed at 6, 12 and 18 months. Results: At baseline, patients in both groups were highly satisfied with their treatment situation and had relatively high sIBDQ values (range: 1–7; CG: 5.12; IG: 4.92). In the intention‐to‐treat (ITT) analysis of the overall sample, there was no significant difference in sIBDQ between groups at the assessment time points. However, a per‐protocol analysis of patients with impaired QoL at baseline (EQ‐VAS < 75 [median]), showed improvement in sIBDQ over 6 months that became significant at month 12 and remained significant through month 18 (baseline: IG 4.24; CG 4.31; 18 months: IG 5.02; CG 4.76; p = 0.017). Conclusion: High baseline satisfaction of IBD patients with treatment and the relatively high baseline sIBDQ values may have contributed to the lack of significant difference in sIBDQ scores for the overall sample. However, patients with impaired QoL derived significant benefit from additional care provided by an IBD nurse specialist, leading to meaningful improvements in sIBDQ over the long term. [ABSTRACT FROM AUTHOR]

This article discusses a study that examined the immune response to SARS-CoV-2 infection and vaccination in patients receiving anti-TNF therapy. The study found that these patients may have lower levels of neutralizing antibodies against different Omicron variants, even after receiving a booster dose. The results suggest the need for improved vaccines and vaccination regimens for this patient population. It is important to note that the study did not examine cellular immunity or provide conclusive evidence on current humoral immunity to SARS-CoV-2. [Extracted from the article]

Summary: Background: Filgotinib 200 mg (FIL200) is an approved treatment for adults with moderately to severely active ulcerative colitis (UC). Aim: To report integrated safety data from the phase 2b/3 SELECTION study (NCT02914522) and its ongoing long‐term extension study SELECTIONLTE (NCT02914535). Methods: Safety outcomes were analysed in adults with moderately to severely active UC who received FIL200, filgotinib 100 mg (FIL100) or placebo once daily throughout the 11‐week SELECTION induction study, the 47‐week SELECTION maintenance study (if applicable) and SELECTIONLTE (if applicable). Exposure‐adjusted incidence rates (EAIRs) per 100 censored patient‐years of exposure with 95% confidence intervals were reported for treatment‐emergent adverse events (AEs). Certain AE data were presented in subgroups, including age and prior biologic exposure status. Results: This interim analysis included 1348 patients representing 3326.2 patient‐years of exposure. Baseline characteristics of patients entering SELECTION were similar across treatment groups. EAIRs for serious infection, thromboembolic events and major adverse cardiovascular events (MACE) were consistently low across treatment groups. Most patients with MACE had cardiovascular risk factors. The EAIR for herpes zoster was numerically higher for FIL200 than for placebo. Infection incidences were numerically higher in biologic‐experienced than biologic‐naive patients. Higher incidences of certain AEs in patients 65 years of age or older were as expected. Four deaths occurred, including three cardiovascular deaths, none of which was considered related to filgotinib. Conclusion: FIL200 and FIL100 were well tolerated with no unexpected safety signals in patients with moderately to severely active UC, regardless of previous biologic exposure or age. ClinicalTrials.gov Identifiers (NCT numbers): NCT02914522, NCT02914535. [ABSTRACT FROM AUTHOR]

Summary: Background: This observational real‐world evidence (RWE) study is based on prospectively collected data from the VEDOIBD registry study. Aim: To compare the effectiveness of vedolizumab and anti‐TNF agents in biologic‐naïve patients with ulcerative colitis (UC) at the end of induction and during maintenance treatment. Methods: Between 2017 and 2020, we enrolled 512 patients with UC starting therapy with vedolizumab or an anti‐TNF agent in 45 IBD centres across Germany. We excluded biologic‐experienced patients and those with missing partial Mayo (pMayo) outcomes; this resulted in a final sample of 314 (182 on vedolizumab and 132 on an anti‐TNF agent). The primary outcome was clinical remission measured using pMayo score; any switch to a different biologic agent was considered an outcome failure (modified ITT analysis). We used propensity score adjustment with inverse probability of treatment weighting to correct for confounding. Results: During induction therapy, clinical remission was relatively low and similar in vedolizumab‐ and anti‐TNF‐treated patients (23% vs. 30.4%, p = 0.204). However, clinical remission rates after two years were significantly higher for vedolizumab‐treated patients than those treated with an anti‐TNF agent (43.2% vs. 25.8%, p < 0.011). Among patients treated with vedolzumab, 29% switched to other biologics, versus 54% who had received an anti‐TNF agent. Conclusion: After two years of treatment, vedolizumab resulted in higher remission rates than anti‐TNF agents. [ABSTRACT FROM AUTHOR]

Summary: Objective: Under the assumption of irreversibility, the Montreal classification provides a unidirectional assessment of the complications and behaviour of Crohn's disease (CD) that does not allow for downstaging. We examined the use of a bidirectional Montreal classification system that can capture disease regression. Design: From the BioCrohn Registry, an inception cohort of patients with CD for ≤12 months duration was defined and followed up for 5‐years. Cumulative probabilities for developing complications were estimated using the Kaplan–Meier method. Potential associations of explanatory variables with disease progression were estimated with Cox regression. Results: Among 393 incident CD patients (of whom 255 completed the entire follow‐up), the 5‐year cumulative probability of developing complications was 41.5% (15.6% and 25.9% for stricturing and penetrating complications respectively). Perianal disease (hazard ratio [95% confidence interval]: 8.45 [4.74–15.07]) and surgical resection of the intestine (2.71 [1.50–4.92]) in the very early phase of the disease were associated with a higher risk of developing a penetrating complication within the 5‐year follow‐up. The use of a bidirectional Montreal classification system which can account for disease regression demonstrated that 90% of patients exhibited inflammatory disease behaviour at 5 years, in contrast to 58%, if the hierarchical, unidirectional Montreal classification system was used. Conclusion: An additional bidirectional disease behaviour assessment capturing reversed or fully controlled complications may provide a more realistic appraisal of the complexity and unmet needs of patients treated with advanced therapies. [ABSTRACT FROM AUTHOR]

Summary: Background: Tofacitinib is the first in class, pan‐JAK inhibitor approved for ulcerative colitis (UC). Clinical efficacy has been shown, but long‐term real‐life endoscopic and histologic data are lacking. Aim: To investigate the effects of tofacitinib in patients with refractory UC focussing on endoscopic, histologic and molecular outcomes, including STAT3 phosphorylation (pSTAT3) detection in the spatial context of mucosal inflammation Methods: We prospectively monitored 59 highly refractory patients (96.7% anti‐TNF exposure, 91.7% vedolizumab exposure) initiating tofacitinib at two IBD referral centres and assessed outcome at the end of induction and after 48 weeks of therapy. Endoscopic improvement was defined as a Mayo endoscopic subscore ≤1, endoscopic and histologic remission as Mayo endoscopic subscore 0 and Nancy histologic score 0. Multiplex immunohistochemistry with multispectral imaging was used to assess pSTAT3. Results: Endoscopic improvement was achieved by 24.4% and 30.5% of patients at weeks 8 and 48, respectively. Endoscopic and histologic remission rates were 11.1%, 23.7 and 16.7%, 21.4%, respectively. Endoscopic improvement at week 8 was significantly associated with treatment continuation in the long‐term (72.7% vs 20.6%, p = 0.003). Although we observed a gradual decrease of mucosal pSTAT3 levels in both remitters and non‐remitters (p < 0.05), no association with treatment outcome could be demonstrated. However, lamina propria pSTAT3 was significantly associated with the Nancy Histologic index (p = 0.004). Conclusion: Tofacitinib can induce and maintain endoscopic and histologic remission in up to one‐quarter of highly refractory UC patients. Longitudinal monitoring of nuclear pSTAT3 in mucosal tissue compartments reflects distinctive on‐target effects, independently of long‐term treatment outcomes. [ABSTRACT FROM AUTHOR]

Background and Aim: Expression of FimH adhesin by invasive Escherichia coli in the gastrointestinal tract of patients with Crohn's disease (CD) facilitates binding to epithelial glycoproteins and release of pro‐inflammatory cytokines. Sibofimloc is a first‐in‐class FimH blocker that showed little systemic absorption in healthy volunteers. The current study evaluated systemic absorption, safety, and effect on inflammatory biomarkers of sibofimloc in patients with CD. Methods: This was an open‐label, multicenter phase 1b study in adults with active CD. In part 1, two patients received a single oral dose of 3000‐mg sibofimloc followed by 1500 mg b.i.d. for 13 days. In part 2, six patients received 1500‐mg sibofimloc b.i.d. for 13 days. Blood was drawn for pharmacokinetic and biomarker analysis, and stool was collected for biomarker and microbiome analysis. Results: Eight patients with active ileal or ileocolonic CD were enrolled into the study. Systemic sibofimloc exposure was low. Sibofimloc was well tolerated with only grade 1–2 events observed. Several pro‐inflammatory biomarkers, including IL‐1β, IL‐6, IL‐8, TNF‐α, IFN‐γ, and calprotectin, were decreased in stool by end of study. Conclusions: This first study of the novel FimH blocker, sibofimloc, in patients with active CD demonstrated minimal systemic exposure with good tolerance, while decreasing several inflammatory biomarkers. EudraCT number: 2017‐003279‐70. [ABSTRACT FROM AUTHOR]

Summary: Background: Recruitment rates for Crohn's disease and ulcerative colitis clinical trials continue to decrease annually. The inability to reach recruitment targets and complete trials has serious implications for stakeholders in the inflammatory bowel disease (IBD) community. Action is required to ensure patients with an unmet medical need have access to new therapies to improve the management of their IBD. Aims: Identify challenges contributing to recruitment decline in IBD clinical trials and propose potential solutions. Methods: PubMed and Google were used to identify literature, regulatory guidelines and conference proceedings related to IBD clinical trials and related concepts. Data on IBD clinical trials conducted between 1989 and 2020 were extracted from the Trialtrove database. Results: Key aspects that may improve recruitment rates were identified. An increasingly patient‐centric approach should be taken to study design including improvements to the readability of key trial documentation and inclusion of patient representatives in trial planning. Placebo is unappealing to patients; approaches including platform trials should be explored to minimise placebo exposure. Non‐invasive imaging, biomarkers and novel digital endpoints should continue to be examined to reduce the burden on patients. Reducing the administrative burden associated with trials via the use of electronic signatures, for example, may benefit study sites and investigators. Changes implemented to IBD trials during the COVID‐19 pandemic provided examples of how trial conduct can be rapidly and constructively adapted. Conclusions: To improve recruitment in Crohn's disease and ulcerative colitis trials, the IBD community should address a broad range of issues related to clinical trial conduct. [ABSTRACT FROM AUTHOR]

Summary: Immune‐mediated chronic inflammatory diseases have emerged as a leading cause of morbidity and mortality in Western countries over the last decades. Although multiple putative factors have been suspected to be causally related to the diseases, their overarching etiology remains unknown. This review article summarizes the current state of scientific knowledge and understanding of the role of non‐receptor tyrosine kinases, with a special focus on the Janus kinase TYK2 in autoimmune and immune mediated diseases as well as on the clinical properties of its inhibition. A panel of experts in the field discussed the scientific evidence and molecular rationale for TYK2 inhibition and its clinical application. Reviewing this meeting, we aim at providing an integrated overview of the clinical profile of TYK2 inhibition and its potential in targeted pharmacological therapy of chronic autoimmune and immune‐mediated diseases, with a special focus on inflammatory diseases of the skin. [ABSTRACT FROM AUTHOR]

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Treatment of patients with biologics such as infliximab may trigger development of antidrug antibodies, which are associated with faster drug clearance, reduced treatment efficacy, and increased risk of infusion‐related reactions. The aim of this study was to identify predictors of baseline infliximab clearance and early antidrug antibody formation. Pharmacokinetic and pharmacokinetic/pharmacodynamic models for infliximab were developed using 21 178 observations from 859 patients from the PLANETRA (ClinicalTrials.gov identifier: NCT01217086) and PLANETAS (NCT01220518) studies in rheumatoid arthritis and ankylosing spondylitis, respectively, to address the specified aims. Infliximab pharmacokinetics were well described by a 2‐compartment model with linear mean estimated baseline clearance of 0.26 L/day. Alongside increased body weight, serum C‐reactive protein, and antidrug antibody concentrations and decreased serum albumin, elevated serum glucose levels predicted higher clearance. In patients with rheumatoid arthritis, baseline infliximab clearance and body weight were the only identified predictors of early antidrug antibody detection. The odds ratio for antidrug antibody detection for each 0.1 L/day increase in baseline infliximab clearance was 1.78 (95% confidence interval, 1.50–2.12); for each 10‐kg increase in body weight, this was 1.19 (1.06–1.33). Here we describe increased serum glucose levels as a novel independent predictor of baseline infliximab clearance. Estimates of baseline infliximab clearance should be incorporated to guide dosing modifications and/or antidrug antibody prophylaxis in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of α‐synuclein and nerve cell loss in striatonigral and olivopontocerebellar structures. Epidemiological and clinical studies have reported potential involvement of autoimmune mechanisms in MSA pathogenesis. However, genetic etiology of this interaction remains unknown. We aimed to investigate genetic overlap between MSA and 7 autoimmune diseases and to identify shared genetic loci. Methods: Genome‐wide association study summary statistics of MSA and 7 autoimmune diseases were combined in cross‐trait conjunctional false discovery rate analysis to explore overlapping genetic background. Expression of selected candidate genes was compared in transgenic MSA mice and wild‐type mice. Genetic variability of candidate genes was further investigated using independent whole‐exome genotyping data from large cohorts of MSA and autoimmune disease patients and healthy controls. Results: We observed substantial polygenic overlap between MSA and inflammatory bowel disease and identified 3 shared genetic loci with leading variants upstream of the DENND1B and RSP04 genes, and in intron of the C7 gene. Further, the C7 gene showed significantly dysregulated expression in the degenerating midbrain of transgenic MSA mice compared with wild‐type mice and had elevated burden of protein‐coding variants in independent MSA and inflammatory bowel disease cohorts. Conclusion: Our study provides evidence of shared genetic etiology between MSA and inflammatory bowel disease with an important role of the C7 gene in both phenotypes, with the implication of immune and gut dysfunction in MSA pathophysiology. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

FKB327 was approved by the European Medicines Agency as a biosimilar to European‐authorized adalimumab (Humira®; AbbVie Inc). Adalimumab is a monoclonal antibody, binding and inhibiting tumor necrosis factor (TNF)‐α with use indicated for several immune‐mediated, chronic, and inflammatory disorders. The approval is based on high similarity in the physicochemical properties between FKB327 and adalimumab. The objective of this study is to assess the biological similarity, with regard to Fab‐ and Fc‐associated functions, and describe the relationship between physicochemical and biological characterization and functional activity. State‐of‐the‐art orthogonal techniques were implemented to assess the structure and function of FKB327. Peptide mapping with liquid chromatography and mass spectrometry, capillary electrophoresis–sodium dodecyl sulfate, ultraviolet circular dichroism, size‐exclusion high‐performance liquid chromatography (HPLC), and cation exchange HPLC were the techniques used to assess structure. Functional activity was assessed with enzyme‐linked immunosorbent assay, surface plasmon resonance, and cell‐based assays. The polypeptide sequence of FKB327 was identical to that of adalimumab. FKB327 also was demonstrated to have a similar secondary and tertiary structure to adalimumab. Posttranslational heterogeneities, along with size and charge variants, were not clinically meaningful. FKB327 binds to TNF‐α, FcγR, the neonatal Fc receptor, and C1q, and induces apoptosis, antibody‐dependent cellular cytotoxicity, and complement‐dependent cytotoxicity. The binding and activity of FKB327 were similar to that of adalimumab. FKB327 shares similar structure and activity with adalimumab. Based on characterization of physicochemical and biological properties, FKB327 is expected to have a similar safety, immunogenicity, and efficacy profile to adalimumab. [ABSTRACT FROM AUTHOR]

Inflammasomes are cytosolic protein complexes, which orchestrate the maturation of active IL‐1β by proteolytic cleavage via caspase‐1. Although many principles of inflammasome activation have been described, mechanisms that limit inflammasome‐dependent immune responses remain poorly defined. Here, we show that the thiol‐specific peroxidase peroxiredoxin‐4 (Prdx4) directly regulates IL‐1β generation by interfering with caspase‐1 activity. We demonstrate that caspase‐1 and Prdx4 form a redox‐sensitive regulatory complex via caspase‐1 cysteine 397 that leads to caspase‐1 sequestration and inactivation. Mice lacking Prdx4 show an increased susceptibility to LPS‐induced septic shock. This effect was phenocopied in mice carrying a conditional deletion of Prdx4 in the myeloid lineage (Prdx4‐ΔLysMCre). Strikingly, we demonstrate that Prdx4 co‐localizes with inflammasome components in extracellular vesicles (EVs) from inflammasome‐activated macrophages. Purified EVs are able to transmit a robust IL‐1β‐dependent inflammatory response in vitro and also in recipient mice in vivo. Loss of Prdx4 boosts the pro‐inflammatory potential of EVs. These findings identify Prdx4 as a critical regulator of inflammasome activity and provide new insights into remote cell‐to‐cell communication function of inflammasomes via macrophage‐derived EVs. Synopsis: This study shows that the thiol‐specific peroxidase peroxiredoxin‐4 (Prdx4) directly regulates IL‐1β generation by interfering with inflammasome activity. Prdx4 forms a redox‐sensitive regulatory complex with the caspase‐1 at the cysteine in position 397 that leads to caspase‐1 sequestration and inactivation. Lack of Prdx4 in myeloid cells leads to elevated IL‐1β levels and increased clinical symptoms in a murine septic shock model.Prdx4 interacts with caspase‐1 in the cytosolic compartment and in extracellular vesicles (EVs) of activated macrophages.Purified EVs from macrophages contain all components of the NLRP3 inflammasome as well as Prdx4 and are able to convey a robust IL‐1β‐dependent inflammatory response in vitro and in vivo.Loss of Prdx4 leads to an increased pro‐inflammatory potential of EVs, indicating a potential role of Prdx4 in the regulation of cell‐to‐cell communication via macrophage‐derived EVs. [ABSTRACT FROM AUTHOR]

Background and Aim: Infliximab has been widely prescribed for treating inflammatory bowel disease (IBD). However, the response rates to infliximab differ among patients. Therefore, we aimed to identify the genetic and clinical markers that predict infliximab response. Methods: A total of 139 Korean patients with IBD who received infliximab were classified according to infliximab response as follows: (i) primary response vs nonresponse and (ii) sustained response vs loss of response. We performed an association study using whole‐exome sequencing data to identify genetic variants associated with infliximab response. Candidate variants were validated in 77 German patients with IBD. Stepwise multivariate logistic regression was performed to identify predictors. Results: We found five candidate variants that were associated with primary nonresponse to infliximab (P < 5 × 10−6). Of the five variants, rs2228273 in ZNF133 was validated in German (combined P = 6.49 × 10−7). We also identified the best genetic variant (rs9144, P = 4.60 × 10−6) associated with the loss of infliximab response. In multivariate regression analysis, rs2228273 (P = 2.10 × 10−5), concurrent azathioprine/6‐mercaptopurine use, and bodyweight at the first infliximab use (< 50 kg) were associated with primary nonresponse. In addition, the Crohn's disease activity index at the first infliximab use and rs9144 (P = 0.001) were independently associated with the loss of response in patients with Crohn's disease. Conclusions: We identified clinical and genetic markers associated with infliximab response in IBD patients. Our findings could provide insights to maximize the efficacy of infliximab therapy in IBD patients. [ABSTRACT FROM AUTHOR]

We identified and tested a novel aspect of human resilience: The daily pursuit of maintenance goals. Taking inspiration from archaeological records, which point at routinized cultural practices as a central resilience factor, we tested whether personal routine practices, governed by maintenance goals, serve a similar function to individuals as traditional practices do to societies. Namely, we hypothesized that maintenance striving increases individuals’ resilient responses to stressful events. Confirming this prediction, a longitudinal Study 1 showed that maintenance striving but not avoidance striving, predicted subsequent increases in well‐being following the third wave of the COVID‐19 pandemic in Germany. Study 2 confirmed our predictions on trait resilience and maintenance versus avoidance motivations in the household and relationship life domains in cross‐sectional data. These studies contribute to the understanding of resilience by demonstrating the benefits of maintenance goals for both situational and trait‐level resilience. [ABSTRACT FROM AUTHOR]

Aim: Recombinant secreted frizzled‐related protein 5 (sFRP5) improved periodontal status in mice. Thus, this study aimed to investigate this finding in human periodontitis using an epidemiological approach. Materials and Methods: sFRP5 and wnt5a concentrations were determined in human serum from the Food Chain Plus cohort using ELISAs. A total of 128 patients with periodontitis and tooth loss and 245 patients with periodontitis without tooth loss were compared to 373 sex‐, smoker‐, age‐ and BMI‐matched individuals in a nested case–control design. Results: Systemic sFRP5 serum levels were significantly lower in patients with periodontitis and tooth loss (2.5 [0.0–10.4] ng/ml, median [IQR]) compared to patients with periodontitis without tooth loss (6.0 [2.5–15.8] ng/ml, median [IQR], p = 0.04] and matched controls (7.0 [2.5–18.3] ng/ml, median [IQR], p = 0.02). No significant differences in sFRP5 serum levels were found among patients with periodontitis without tooth loss (6.0 [2.5–15.8] ng/ml, median [IQR]) and controls (3.1 [0.0–10.6] ng/ml, median [IQR], p = 0.06). Conclusions: sFRP5 might serve as a novel biomarker for periodontitis severity. Modulating the inflammatory background of severe forms of periodontitis, in the time of precision medicine, needs to be revealed in further studies. [ABSTRACT FROM AUTHOR]

Aim The intronic variant rs4252120 in the plasminogen gene ( PLG) is known to be associated with aggressive periodontitis (AgP) and atherosclerosis. Here, we examined the chromosomal region spanning PLG for associations with both chronic periodontitis (CP) and AgP. Materials and Methods The association of PLG candidate rs4252120 was tested in a German case-control sample of 1,419 CP cases using the genotyping assay hCV11225947 and 4,562 controls, genotyped with HumanOmni BeadChips. The German and Dutch sample of AgP cases ( N = 851) and controls ( N = 6,836) were genotyped with HumanOmni BeadChips. The North American CP sample ( N = 2,681 cases, 1,823 controls) was previously genotyped on the Genome-Wide Human SNP Array 6.0. Genotypes were imputed (software Impute v2), and association tests were performed using an additive genetic model adjusting for sex and smoking. Results Rs4252120 was not associated with CP. However, a haplotype block downstream of PLG and not in linkage disequilibrium with rs4252120 ( r2 = .08) was associated with both AgP (rs1247559; p = .002, odds ratio [OR] = 1.33) and CP ( p = .02, OR = 1.15). That locus was also significantly associated with PLG expression in osteoblasts ( p = 6.9 × 10−5). Conclusions Our findings support a role of genetic variants in PLG in the aetiology of periodontitis. [ABSTRACT FROM AUTHOR]

Human longevity is a complex phenotype influenced by genetic and environmental components. Unraveling the contribution of genetic vs. nongenetic factors to longevity is a challenging task. Here, we conducted a large-scale RNA-sequencing-based expression quantitative trait loci study ( eQTL) with subsequent heritability analysis. The investigation was performed on blood samples from 244 individuals from Germany and Denmark, representing various age groups including long-lived subjects up to the age of 104 years. Our eQTL-based approach revealed for the first time that human longevity is associated with a depletion of metabolic pathways in a genotype-dependent and independent manner. Further analyses indicated that 20% of the differentially expressed genes are influenced by genetic variants in cis. The subsequent study of twins showed that the transcriptional activity of a third of the differentially regulated genes is heritable. These findings suggest that longevity-associated biological processes such as altered metabolism are, to a certain extent, also the driving force of longevity rather than just a consequence of old age. [ABSTRACT FROM AUTHOR]

Variation in xylem vessel diameter is one of the most important parameters when evaluating plant water relations. This review provides a synthesis of the ecophysiological implications of variation in lumen diameter together with a summary of our current understanding of vessel development and its endogenous regulation. We analyzed inter-specific variation of the mean hydraulic vessel diameter ( Dv) across biomes, intra-specific variation of Dv under natural and controlled conditions, and intra-plant variation. We found that the Dv measured in young branches tends to stay below 30 µm in regions experiencing winter frost, whereas it is highly variable in the tropical rainforest. Within a plant, the widest vessels are often found in the trunk and in large roots; smaller diameters have been reported for leaves and small lateral roots. Dv varies in response to environmental factors and is not only a function of plant size. Despite the wealth of data on vessel diameter variation, the regulation of diameter is poorly understood. Polar auxin transport through the vascular cambium is a key regulator linking foliar and xylem development. Limited evidence suggests that auxin transport is also a determinant of vessel diameter. The role of auxin in cell expansion and in establishing longitudinal continuity during secondary growth deserve further study. [ABSTRACT FROM AUTHOR]

Hybrid poplars are an important renewable forest resource known for their high productivity. At the same time, they are highly vulnerable to water stress. Identifying traits that can serve as indicators for growth performance remains an important task, particularly under field conditions. Understanding which trait combinations translate to improved productivity is key in order to satisfy the demand for poplar wood in an uncertain future climate. In this study, we compared hydraulic and leaf traits among five hybrid poplar clones at 10 plantations in central Alberta. We also assessed the variation of these traits between 2- to 3-year-old branches from the lower to mid-crown and current-year long shoots from the mid to upper crown. Our results showed that (1) hybrid poplars differed in key hydraulic parameters between branch type, (2) variation of hydraulic traits among clones was relatively large for some clones and less for others, and (3) strong relationships between measured hydraulic traits, such as vessel diameter, cavitation resistance, xylem-specific and leaf-specific conductivity and leaf area, were observed. Our results suggest that leaf size could serve as an additional screening tool when selecting for drought-tolerant genotypes in forest management and tree improvement programmes. [ABSTRACT FROM AUTHOR]

Xylem vessel diameters represent an important plant hydraulic trait to ensure sufficient water supply from the roots to the leaves. The ability to adjust the hydraulic pathway to environmental cues is key in order to satisfy transpirational demands and maximize growth and survival., We evaluated the variability of vessel diameters in trembling aspen in a reciprocal transplant experiment. We tested six provenances from three ecological regions of North America planted at four test sites in western Canada. All test sites were established at the same time with the same provenances arranged in a randomized complete block design., Vessel diameter showed a strong interaction of population and test site suggesting a high degree of phenotypic plasticity in this trait. Gaussian kernel density estimates support plastic as well as genetic contributions in vessel diameter control trending from bimodal distributions at the most northern test site towards unimodal distributions at the warmest and mildest test site., Furthermore, we used test site-specific climate data in form of a 2-year, 5-year and 10-year average of 21 directly and derived climatic variables and found that average site-specific vessel diameters correlated strongly with summer moisture availability. A previously found negative relationship with vessel diameter and tree height in central Alberta was also found at two other boreal test sites but reversed at a wetter and milder sub-boreal test site., In summary, vessel diameters were highly plastic in response to different environments and varied with summer moisture availability. The variability of vessel diameter and tree height correlations suggests that vessel diameter alone cannot serve as a reliable proxy for long-term growth performance beyond boreal environments. Instead, selecting aspen populations with a high degree of plasticity in this trait appears to be the safest option for assisted migration and seed transfer programmes under climate change. [ABSTRACT FROM AUTHOR]

Background Non-alcoholic fatty liver disease ( NAFLD) is the most common chronic liver disorder in industrialized countries, yet its pathophysiology is incompletely understood. Small-molecule metabolite screens may offer new insights into disease mechanisms and reveal new treatment targets. Methods Discovery ( N = 33) and replication ( N = 66) of liver biopsies spanning the range from normal liver histology to non-alcoholic steatohepatitis ( NASH) were ascertained ensuring rapid freezing under 30 s in patients. 252 metabolites were assessed using GC/ MS. Replicated metabolites were evaluated in a murine high-fat diet model of NAFLD. Results In a two-stage metabolic screening, hydroquinone ( HQ, pcombined = 3.0 × 10−4) and nicotinic acid ( NA, pcombined = 3.9 × 10−9) were inversely correlated with histological NAFLD severity. A murine high-fat diet model of NAFLD demonstrated a protective effect of these two substances against NAFLD: Supplementation with 1% HQ reduced only liver steatosis, whereas 0.6% NA reduced both liver fat content and serum transaminase levels and induced a complex regulatory network of genes linked to NALFD pathogenesis in a global expression pathway analysis. Human nutritional intake of NA equivalent was also consistent with a protective effect of NA against NASH progression. Conclusion This first small-molecular screen of human liver tissue identified two replicated protective metabolites. Either the use of NA or targeting its regulatory pathways might be explored to treat or prevent human NAFLD. [ABSTRACT FROM AUTHOR]

Aim Epidemiological and clinical studies indicated a relationship of periodontitis with rheumatoid arthritis ( RA). We aimed to identify shared genetic susceptibility loci of RA and periodontitis. Materials and Methods Forty-seven risk genes of genome-wide significance of RA and SLE were genotyped in a German case-control sample of aggressive periodontitis (AgP), using Immunochip genotyping arrays (Illumina, 600 cases, 1440 controls) and Affymetrix 500 K Genotyping Arrays (280 cases and 983 controls). Significant associations were replicated in 168 Dutch AgP cases and 679 controls and adjusted for the confounders smoking and sex. Results Variants at IRF5 and PRDM1 showed association with AgP. Upon covariate adjustment for smoking and sex, the most strongly associated variant at IRF5 was the rare variant rs62481981 ( ppooled = 0.0012, odds ratio [ OR] = 3.1, 95% confidence interval [95% CI] = 1.6-6.1; 801 cases, 1476 controls).Within PRDM1 it was rs6923419 ( ppooled = 0.004, OR = 0.7, 95% CI = 0.6-0.9; 833 cases, 1440 controls). The associations lost significance after correction for multiple testing in the replication. Both genes are implicated in beta-interferon signalling and are also genome-wide associated with SLE and inflammatory bowel disease. Conclusion The study gives no definite evidence for a pathogenic genetic link of periodontitis and RA but suggests IRF5 and PRDM1 as shared susceptibility factors. [ABSTRACT FROM AUTHOR]

Aim Periodontitis ( PD) is influenced by genetic as well as lifestyle and socio-economic factors. Epidemiological studies show that men are at greater risk of severe forms of PD, suggesting interplay between sex and genetic factors. We aimed to systematically analyse patients with aggressive periodontitis (AgP) for gene-sex interactions. Materials and Methods Three hundred and twenty-nine German AgP cases and 983 controls were genotyped with Affymetrix 500K Arrays and were analysed by logistic regression analysis. The most significant gene-sex interaction was replicated in an independent sample of 382 German/Austrian AgP cases and 489 controls. Results Ten single-nucleotide polymorphisms ( SNPs) in strong linkage disequilibrium ( r 2 > 0.85) upstream the gene neuropeptide Y ( NPY) suggested gene-sex interaction ( p < 5 × 10−5). SNP rs198712 showed the strongest association in interaction with sex ( p = 5.4 × 10−6) with odds ratios in males and females of 1.63 and 0.69 respectively. In the replication, interaction of sex with rs198712 was verified with p = 0.022 (pooled p = 4.03 × 10−6) and similar genetic effects. Analysis of chromatin elements from ENCODE data revealed tissue-specific transcription at the associated non-coding region. Conclusion This study is the first to observe a sexually dimorphic role of alleles at NPY in humans and support previous genome-wide findings of a role of NPY in severe PD. [ABSTRACT FROM AUTHOR]

Aim Identification of variants within genes SLC23A1 and SLC23A2 coding for vitamin C transporter proteins associated with aggressive (AgP) and chronic periodontitis ( CP). Material and Methods Employment of three independent case-control samples of AgP (I. 283 cases, 979 controls; II. 417 cases, 1912 controls; III. 164 cases, 357 controls) and one sample of CP (1359 cases, 1296 controls). Results Stage 1: Among the tested single-nucleotide polymorphisms ( SNPs), the rare allele ( RA) of rs6596473 in SLC23A1 showed nominal significant association with AgP ( p = 0.026, odds ratio [ OR] 1.26, and a highly similar minor allele frequency between different control panels. Stage 2: rs6596473 showed no significant association with AgP in the replication with the German and Dutch case-control samples. After pooling the German AgP populations (674 cases, 2891 controls) to significantly increase the statistical power ( SP = 0.81), rs6596473 RA showed significant association with AgP prior to and upon adjustment with the covariates smoking and gender with padj = 0.005, OR = 1.35. Stage 3: RA of rs6596473 showed no significant association with severe CP. Conclusion SNP rs6596473 of SLC23A1 is suggested to be associated with AgP. These results add to previous reports that vitamin C plays a role in the pathogenesis of periodontitis. [ABSTRACT FROM AUTHOR]

According to the range limit hypothesis, the distribution of many temperate species is restricted by a trade-off between their capacity to survive winter extremes in the north (or high elevation) and their ability to compete with better-adapted species in the south (or low elevation range limits). This trade-off has important implications in forestry, particularly in the context of managed seed movement under climate change., In this study, we aim to quantify trade-offs among growth, frost hardiness and timing of leaf senescence and bud break in populations of trembling aspen, Populus tremuloides Michx., which were observed in a large reciprocal transplant experiment across five planting sites in western Canada, including additional provenances from Minnesota., After 10 years, we found pronounced increases in productivity as a result of long-distance transfers in a north-west direction. For example, provenances moved 1600 km north-west from Minnesota to central Alberta (a shift of 7° latitude to the north) produced almost twice the biomass of local sources. Similarly, provenances moved 800 km from central Alberta to north-east British Columbia (4° latitude north) also produced twice the biomass of local sources., We further found that increased growth was not associated with lower survival rates. Bud break in provenances transferred north-west generally occurred slightly later than in local sources, suggesting decreased risk of spring frost injury. Leaf abscission was later in provenances transferred in a north-west direction, but they appeared to be very frost hardy, well ahead of very rare early fall frost events., Synthesis and applications. This study demonstrated that assisted migration prescriptions have considerable potential to enhance forest productivity. In the case of aspen, even long-distance seed transfers in a north-west direction were successful. We conclude that benefits in productivity outweigh potential risks associated with northward transfer of aspen planting stock under both current and projected future climate conditions. [ABSTRACT FROM AUTHOR]

ABSTRACT In recent years, thousands of hectares of hybrid poplar plantations have been established in Canada for the purpose of carbon sequestration and wood production. However, boreal planting environments pose special challenges that may compromise the long-term survival and productivity of such plantations. In this study, we evaluated the effect of winter stress, that is, frequent freeze-thaw and extreme cold events, on growth and survival of 47 hybrid poplar clones in a long-term field experiment. We further assessed physiological and structural traits that are potentially important for cold tolerance for a selected set of seven clones. We found that trees with narrow xylem vessels showed reduced freezing-induced embolism and showed superior productivity after 16 growing seasons. With respect to cold hardiness of living tissues, we only observed small differences among clones in early autumn, which were nonetheless significantly correlated to growth. Maximum winter cold hardiness and the timing of leaf senescence and budbreak were not related to growth or survival. In conclusion, our data suggest that reduction of freezing-induced embolism due to small vessel diameters is an essential adaptive trait to ensure long-term productivity of hybrid poplar plantations in boreal planting environments. [ABSTRACT FROM AUTHOR]

Purpose Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 ( NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies ( IGEs). Methods We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio ( OR) 9.91, 95% confidence interval ( CI) 1.92-51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes. [ABSTRACT FROM AUTHOR]

The transition from hunting and gathering to agriculture in Europe is associated with demographic changes that may have shifted the human gene pool of the region as a result of an influx of Neolithic farmers from the Near East. However, the genetic composition of populations after the earliest Neolithic, when a diverse mosaic of societies that had been fully engaged in agriculture for some time appeared in central Europe, is poorly known. At this period during the Late Neolithic (ca. 2,800-2,000 BC), regionally distinctive burial patterns associated with two different cultural groups emerge, Bell Beaker and Corded Ware, and may reflect differences in how these societies were organized. Ancient DNA analyses of human remains from the Late Neolithic Bell Beaker site of Kromsdorf, Germany showed distinct mitochondrial haplotypes for six individuals, which were classified under the haplogroups I1, K1, T1, U2, U5, and W5, and two males were identified as belonging to the Y haplogroup R1b. In contrast to other Late Neolithic societies in Europe emphasizing maintenance of biological relatedness in mortuary contexts, the diversity of maternal haplotypes evident at Kromsdorf suggests that burial practices of Bell Beaker communities operated outside of social norms based on shared maternal lineages. Furthermore, our data, along with those from previous studies, indicate that modern U5-lineages may have received little, if any, contribution from the Mesolithic or Neolithic mitochondrial gene pool. Am J Phys Anthropol 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aim Involvement of TLR2 in the pathophysiology of periodontitis has widely been discussed, but hitherto, no validated genetic associations were reported. Previous association studies lacked sufficient statistical power and adequate haplotype information to draw unambiguous conclusions. The aim of this study was to comprehensively investigate TLR2 linkage disequilibrium ( LD) regions for their potential associations with periodontitis in two large analysis populations of aggressive ( AgP) and chronic periodontitis ( CP) of North West European descent. Materials and methods The study population comprised 598 AgP patients, 914 CP patients and 1804 healthy controls. Analysis of TLR2 LD regions was performed with haplotype tagging SNPs (tagSNPs) using SNPlex and TaqMan genotyping assays. Genotypic, dominant, multiplicative, and recessive genetic models were tested. The genotypes were adjusted for the covariates smoking, diabetes, and gender. Resequencing was performed by Sanger technology. Results Upon covariate adjustment and correction for multiple testing, no tagSNPs showed significant associations with AgP or CP. Targeted resequencing of exon 3 in 47 AgP cases identified carriership of two common and three rare variants. Conclusion Common LD regions of TLR2 do not show genetic associations with periodontitis in the North West European population. Resequencing of exon 3 could not identify disease-associated rare variants in TLR2. [ABSTRACT FROM AUTHOR]

Abberrant DNA methylation is one of the hallmarks of cancerogenesis. Our study aims to delineate differential DNA methylation in cirrhosis and hepatic cancerogenesis. Patterns of methylation of 27,578 individual CpG loci in 12 hepatocellular carcinomas (HCCs), 15 cirrhotic controls and 12 normal liver samples were investigated using an array-based technology. A supervised principal component analysis (PCA) revealed 167 hypomethylated loci and 100 hypermethylated loci in cirrhosis and HCC as compared to normal controls. Thus, these loci show a 'cirrhotic' methylation pattern that is maintained in HCC. In pairwise supervised PCAs between normal liver, cirrhosis and HCC, eight loci were significantly changed in all analyses differentiating the three groups ( p < 0.0001). Of these, five loci showed highest methylation levels in HCC and lowest in control tissue ( LOC55908, CELSR1, CRMP1, GNRH2, ALOX12 and ANGPTL7), whereas two loci showed the opposite direction of change ( SPRR3 and TNFSF15). Genes hypermethylated between normal liver to cirrhosis, which maintain this methylation pattern during the development of HCC, are depleted for CpG islands, high CpG content promoters and polycomb repressive complex 2 (PRC2) targets in embryonic stem cells. In contrast, genes selectively hypermethylated in HCC as compared to nonmalignant samples showed an enrichment of CpG islands, high CpG content promoters and PRC2 target genes ( p < 0.0001). Cirrhosis and HCC show distinct patterns of differential methylation with regards to promoter structure, PRC2 targets and CpG islands. [ABSTRACT FROM AUTHOR]

The allele ε4 of apolipoprotein E (APOE), which is a key regulator of lipid metabolism, represents a risk factor for cardiovascular diseases and Alzheimer's disease. Despite its adverse effects, the allele is common and shows a nonrandom global distribution that is thought to be the result of evolutionary adaptation. One hypothesis proposes that the APOE ε4 allele protects against vitamin D deficiency. Here we present, for the first time, experimental and epidemiological evidence that the APOE ε4 allele is indeed associated with higher serum vitamin D [25(OH)D] levels. In APOE4 targeted replacement mice, significantly higher 25(OH)D levels were found compared with those in APOE2 and APOE3 mice (70.9 vs. 41.8 and 27.8 nM, P<0.05). Furthermore, multivariate adjusted models show a positive association of the APOE e4 allele with 25(OH)D levels in a small collective of human subjects (n=93; P=0.072) and a general population sample (n=699; P=0.003). The novel link suggests ε4 as a modulator of vitamin D status. Although this result agrees well with evolutionary aspects, it appears contradictory with regard to chronic diseases, especially cardiovascular disease. Large prospective cohort studies are now needed to investigate the potential implications of this finding for chronic disease risks. [ABSTRACT FROM AUTHOR]

Summary [ABSTRACT FROM AUTHOR]

Intensive forestry systems and breeding programs often include either native aspen or hybrid poplar clones, and performance and trait evaluations are mostly made within these two groups. Here, we assessed how traits with potential adaptive value varied within and across these two plant groups. Variation in nine hydraulic and wood anatomical traits as well as growth were measured in selected aspen and hybrid poplar genotypes grown at a boreal planting site in Alberta, Canada. Variability in these traits was statistically evaluated based on a blocked experimental design. We found that genotypes of trembling aspen were more resistant to cavitation, exhibited more negative water potentials, and were more water-use-efficient than hybrid poplars. Under the boreal field test conditions, which included major regional droughts, height growth was negatively correlated with branch vessel diameter (Dv) in both aspen and hybrid poplars and differences in Dv were highly conserved in aspen trees from different provenances. Differences between the hybrid poplars and aspen provenances suggest that these two groups employ different water-use strategies. The data also suggest that vessel diameter may be a key trait in evaluating growth performance in a boreal environment. [ABSTRACT FROM AUTHOR]

The human gastrointestinal tract microbiota, despite its key roles in health and disease, remains a diverse, variable and poorly understood entity. Current surveys reveal a multitude of undefined bacterial taxa and a low diversity of methanogenic archaea. In an analysis of the microbiota in colonic mucosal biopsies from patients with inflammatory bowel disease we found 16S rDNA sequences representing a phylogenetically rich diversity of halophilic archaea from the Halobacteriaceae (haloarchaea), including novel phylotypes. As the human colon is not considered a salty environment and haloarchaea are described as extreme halophiles, we evaluated and further discarded the possibility that these sequences originated from pre-colonoscopy saline lavage solutions. Furthermore, aerobic enrichment cultures prepared from a patient biopsy at low salinity (2.5% NaCl) yielded haloarchaeal sequence types. Microscopic observation after fluorescence in situ hybridization provided evidence of the presence of viable archaeal cells in these cultures. These results prove the survival of haloarchaea in the digestive system and suggest that they may be members of the mucosal microbiota, even if present in low numbers in comparison with methanogenic archaea. Investigation of a potential physiological basis of this association may lead to new insights into gastrointestinal health and disease. [ABSTRACT FROM AUTHOR]

Copyright of Movement Disorders is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Keywords: hydraulic efficiency; hydraulic safety; plant hydraulics; tradeoff; xylem EN hydraulic efficiency hydraulic safety plant hydraulics tradeoff xylem 1156 1158 3 04/19/21 20160915 NES 160915 We appreciate Bittencourt et al.'s (2016; in this issue of I New Phytologist i , pp. 1152-1155) constructive contributions following our paper, Gleason I et al i . Considering angiosperms, it is likely that nonvessel tissue fractions influence the safety-efficiency tradeoff indirectly (e.g. via their contribution to xylem capacitance, or whole-plant growth), rather than being forced by limited xylem space. On research priorities to advance understanding of the safety-efficiency tradeoff in xylem: A response to Bittencourt et al.'s (2016) comment 'On xylem hydraulic efficiencies, wood space-use and the safety-efficiency tradeoff' As such, vessel lumen fraction, vessel diameter, and vessel frequency are largely uncoupled from nonvessel tissue fractions across self-supporting angiosperm species (Zanne I et al i .,), and are therefore unlikely to trade off with mechanical safety and hydraulic efficiency (or safety). [Extracted from the article]

Objective The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined. Methods We carried out whole-genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single-nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts. Results We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 × 10−7), PDXK (vitamin B6/dopamine metabolism, p = 3.27 × 10−6), SRGAP3 (axon guidance, p = 5.65 × 10−6), and TRAPPC4 (vesicle transport, p = 5.81 × 10−6). We identified a DNA variant ( rs2010795) in PDXK associated with an increased risk of PD in the German cohort ( p = 0.00032). This association was confirmed in the British ( p = 0.028) and Italian ( p = 0.0025) cohorts individually and reached a combined value of p = 1.2 × 10−7 (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18-1.44). Interpretation We provide an example of how microgenomic genome-wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD. Ann Neurol 2009;66:792-798 [ABSTRACT FROM AUTHOR]

Osteopontin (OPN) is characterized as a major amplifier of Th1-immune responses. However, its role in intestinal inflammation is currently unknown. We found considerably raised OPN levels in blood of wild-type (WT) mice with dextran sodium sulfate (DSS)-induced colitis. To identify the role of this mediator in intestinal inflammation, we analysed experimental colitis in OPN-deficient (OPN−/−) mice. In the acute phase of colitis these mice showed more extensive colonic ulcerations and mucosal destruction than WT mice, which was abrogated by application of soluble OPN. Within the OPN−/– mice, infiltrating macrophages were not activated and showed impaired phagocytosis. Reduced mRNA expression of interleukin (IL)-1 β and matrix metalloproteinases was found in acute colitis of OPN−/– mice. This was associated with decreased blood levels of IL-22, a Th17 cytokine that may mediate epithelial regeneration. However, OPN–/– mice showed increased serum levels of tumour necrosis factor (TNF)-α, which could be due to systemically present lipopolysaccharide translocated to the gut. In contrast to acute colitis, during chronic DSS-colitis, which is driven by a Th1 response of the lamina propria infiltrates, OPN−/– mice were protected from mucosal inflammation and demonstrated lower serum levels of IL-12 than WT mice. Furthermore, neutralization of OPN in WT mice abrogated colitis. Lastly, we demonstrate that in patients with active Crohn's disease OPN serum concentration correlated significantly with disease activity. Taken together, we postulate a dual function of OPN in intestinal inflammation: During acute inflammation OPN seems to activate innate immunity, reduces tissue damage and initiates mucosal repair whereas during chronic inflammation it promotes the Th1 response and strengthens inflammation. [ABSTRACT FROM AUTHOR]

Copyright of Movement Disorders is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Bacterial DNA has been found in coronary plaques and it has therefore been concluded that bacteria may play a role as trigger factors in the chronic inflammatory process underlying coronary atherosclerosis. However, the microbial spectrum is complex and it is not known whether microorganisms other than bacteria are involved in coronary disease. Fungal 18S rDNA signatures were systematically investigated in atherosclerotic tissue obtained through catheter-based atherectomy of 38 patients and controls (unaffected coronary arteries) using clone libraries, denaturating gradient gel analysis (DGGE), in situ hybridization and fluorescence in situ hybridization (FISH). Fungal DNA was found in 35 of 38 (92.11%) coronary heart disease patients by either polymerase chain reaction (PCR) with universal primers or in situ hybridization analysis ( n = 5), but not in any control sample. In a clone library with more than 350 sequenced clones from pooled patient DNA, an overall richness of 19 different fungal phylotypes could be observed. Fungal profiles of coronary heart disease patients obtained by DGGE analysis showed a median richness of fungal species of 5 (range from 2 to 9) with a high interindividual variability (mean similarity 18.83%). For the first time, the presence of fungal components in atherosclerotic plaques has been demonstrated. Coronary atheromatous plaques harbour diverse and variable fungal communities suggesting a polymicrobial contribution to the chronic inflammatory aetiology. [ABSTRACT FROM AUTHOR]